1. Field of the Invention
The present invention generally relates to the treatment of dermatological conditions and, more specifically, to the treatment of conditions related to aging or photodamaged skin, by topical application of a composition comprising a peptide manganese complex.
2. Description of the Related Art
Aging and photodamage result in a number of changes in the structure and function of skin. Primary among these changes is a thinning of the skin due to lower levels of collagen, elastin and other components of the skin's connective tissue. Lower levels of synthesis and activity (i.e., proliferation and viability) of fibroblasts responsible for the synthesis of collagen and elastin are also characteristic of aging skin.
There are many treatments available to alter the appearance of aging skin, including various creams and oils that primarily serve to rehydrate the skin. Such re-hydration temporarily lessens the appearance of fine line and wrinkles. There are also numerous compounds that enhance the synthesis of certain components of the skin, such as collagen and glycosaminoglycans, and the underlying connective tissue. For example, all-trans retinoic acid has been shown to stimulate collagen synthesis in UVB irradiated skin (see Chen S. et al., Invest. Dermatol. 98(2):248–254 (1992)) and topical growth factors have been shown to increase collagen synthesis and produce a thickening of the epidermis (see Fitzpatrick R. E. at al., Journal of Cosmetic and Laser Therapy 5(1):25–34 (2003)). Ascorbic acid and its derivatives have also been shown to stimulate increases in collagen synthesis (see Geesin J. C. et al., Skin Pharmacology 6(1):65–71 (1993) and Murad S. et al., J. Invest. Dermatol. 81(2):158–162 (1983) Furthermore, it has been shown that the biosynthesis of another component of the extracellular matrix, elastin, is increased by topical application of L-fucose or certain fucose-rich polysaccharides (see Robert L. et al., Biomedicine & Pharmacotherapy 58(2):123–128 (2004)). Nonetheless, aging skin, and the corresponding fine lines, wrinkles and other external appearances, remain a concern.
Manganese is an essential nutrient involved in the formation of bone and in amino acid, cholesterol, and carbohydrate metabolism. Enzymes, which utilize manganese for activity, include arginase, glutamine synthetase, manganese superoxide dismutase, prolidase, and some carbohydrate transferases. The Adequate Intake levels for men and women have been set at 2.3 and 1.8 mg/day respectively. The enzyme Superoxide Dismutase is one of the most important defenses against oxidative damage in the body. There are two types in humans, namely, the Cu-Zn Superoxide Dismutase (SOD1), which is found mainly in the cytosol of the cell, and the Mn-Superoxide Dismutase (SOD2), which is found in the mitochondria (see Kobayashi et al., Acta Dermato-Venereologica 73(1):41–45 (1993)).
Small molecular weight complexes of manganese have been shown to possess superoxide dismutase activity. For example, U.S. Pat. Nos. 5,223,538 and 5,227,405 to Fridovich et al. describe water-soluble manganese complexes useful to reduce and prevent superoxide radical induced toxicity. In addition, U.S. Pat. No. 5,118,665 to Pickart discloses peptide manganese complexes with superoxide dismutase activity useful for enhancing or restoring the resistance of an animal to oxidative or inflammatory damage.
Manganese is also an important component of the enzyme Prolidase. This is a manganese dependent exopeptidase (i.e., a protease which cuts off amino acids from the end of the peptide chain). Prolidase cleaves proline from peptides inside the cell and provides a vital source of proline for new collagen synthesis. The addition of manganese to increase intracellular manganese increases the activity of Prolidase in deficient cells (see Hechtman et al., Pediatric Research 24(6):709–712 (1998)). Another manganese requiring enzyme is Arginase. Arginase is an enzyme responsible for the conversion of the amino acid arginine to urea in keratinocytes. The addition of L-arginine and manganese to keratinocyte cultures results in the increase of urea synthesis (see Wohlrab et al., Skin Pharmacology and Applied Skin Physiology 15(1):44–54 (2002)).
Although there have been advances in the art, there remains a need for more effective and otherwise improved methods for treating dermatological conditions related to aging or photodamaged skin, such as fine lines and wrinkles. In particular, there remains a need for treatment methods that provide for increased proliferation and viability of dermal fibroblasts and other components of the dermal connective tissue, such as collagen. The present invention addresses these needs and provides further related advantages.